The present invention relates to novel polyamines, compositions containing them and their use in the treatment of neurotrauma such as stroke.
Polyamines as a class of compounds have been reported to possess a wide range of activities both within and external to the central nervous system. Such activities include modulation of postsynaptic receptors, such as nicotinic, glutamic and N-methyl-D-aspartate receptors, modulation of calcium regulatory processes as well as antiplatelet, antiinflammatory and anticoagulant activity.
Various polyamine containing molecules have been synthesized and screened in a variety of animal models of disorders of the central nervous system. Many of these compounds have been based on toxins extracted from spiders such as A. aperta and Argiope labata and the wasp P. triangulum. These compounds comprise a long poly(aminoalkane) chain linked to an aromatic or heterocyclic group through a carbonyl group.
Guanidine derivatives of polyamines, e.g. SFTX-33 have been reported as voltage-sensitive calcium channel blockers and EAA antagonists capable of binding at the PCP site on the NMDA receptor. U.S. Pat. No. 4,906,779 (Oregon 1990). Spergualine and deoxypergualine has been reported (R. J. Bergeron, J. S. McManis, J. Org. Chem., 52, 1700 (1987); Drug Fut., 16, 165 (1991)) to possess immunosuppressant activity and beneficial effect in the treatment of Multiple Sclerosis. ##STR2##
Gilad G et al. (Life Sci. (1989) 44 1963-1969 and Exp. Neurol. (1991) 111 349-355) have described activity of the polyamines spermine, spermidine and putrescine in protecting.against ischemia induced nerve cell death in gerbils.
Disadvantages associated with using the simple polyamines described in Gilad G et al. relate to transport through biological membranes and various toxic side effects that would hinder these compounds from proceeding to clinical use.
Accordingly, the present invention provides derivatives of spermine, spermidine, and putrescine and guanidine derivatives thereof that retain the activity of the polyamine but display fewer undesirable side effects.